Central nervous system involvement in late-onset Pompe disease: clues from neuroimaging and neuropsychological analysis.

BACKGROUND AND PURPOSE: Late-onset Pompe disease (LOPD) is a rare, multisystem disorder that is well established to mainly impair skeletal muscle function. Systematic studies exploring brain functions in LOPD are lacking. The aim of this study was to detect morphological and functional brain alterations as well as neuropsychological impairment in LOPD. METHODS: We studied 21 patients (10 male, mean age 49 ± 18.4 years) with defined diagnosis of LOPD, divided into two groups: one with pre-symptomatic hyperCKemia with no muscle weakness and the second with limb-girdle muscle weakness. All patients underwent 3T magnetic resonance imaging (MRI) to obtain morphological/angiographic evaluation as well as normalized cortical brain volume and resting-state functional MRI. Fazekas score was applied to quantify white matter lesions, whereas Smoker's criteria were used to examine dolichoectasia. A complete neuropsychological assessment was performed. RESULTS: The MRI data showed that 12/21 patients (57%) demonstrated signs of cerebral vasculopathy, with a Fazekas score >2 in 67%. According to Smoker's criteria, 11/21 patients (52%) had a dolichoectasia of the vertebrobasilar system; an intracranial aneurysm was detected in 3/21 patients (14%). Resting-state functional MRI demonstrated significantly decreased brain connectivity in the salience network with a more relevant reduction in the bilateral middle and superior frontal gyrus. Gray matter atrophy correlated with age and disease duration. A mild impairment in executive functions was also identified. CONCLUSIONS: In this LOPD cohort the results showed morphological and functional brain alterations with mild neuropsychological dysfunction, mainly in the limb-girdle muscle weakness group. Cerebrovascular alterations seemed to be not related to common risk factors, suggesting a major role of enzymatic deficiency in the pathogenesis of brain abnormalities.

Cortical reorganization in multiple sclerosis after intrathecal baclofen therapy.

Our objective was to assess the role of Intrathecal Baclofen Therapy (ITB) in the cortical reorganization in a patient affected by multiple sclerosis (MS) undergoing physical therapy. We reported a case of a woman affected by MS and severe spasticity, who performed an fMRI examination, before and after the ITB implantation. The subject showed controlateral motor cortex activation after motor task. After a month of ITB implantation, patient showed ipsilateral and controlateral motor cortex activation although with a broader extension. fMRI examination supported the hypothesis of a central influence in patients who undergo physiotherapy and therapy with ITB.

Recombinant human erythropoietin in pediatric patients: efficacy in facilitating autologous blood donation in spinal deformity surgery.

Preoperative autologous blood donation (PABD) is a widely used practice in orthopaedic elective surgery, but many pediatric patients are unable to complete the program of pre-deposit. Twenty-three consecutive patients undergoing spinal surgery for scoliosis received 6 administrations of 10000U of recombinant human erythropoietin (rHuEpo). Preop hemoglobin (Hb) levels and the numbers of collected and of autologous and allogeneic blood transfused units were determined. These results were compared with a previously-operated group of 28 patients, who differed only by the absence of concomitant erythropoietin therapy. Significant higher numbers of collected blood units and Hb levels were measured, and all of the patients completed the PABD program. A significantly lower requirement for allogeneic blood in the <> group was observed: 1 vs 9 patients (4.3%-32.1%; p < 0.001). The study documents the efficacy of rHuEpo in facilitating the completion of a PABD program and in reducing exposure to allogeneic blood in pediatric patients undergoing corrective spinal surgery.

Acetabular reinforcement rings and bone allografts in the reconstructive treatment of periprosthetic bone loss.

Medium-term results in the treatment of acetabular bone loss using bulk and/or morselized bone allografts supported by acetabular reinforcement rings are reported. A total of 164 hips in 157 patients were treated by means of this reconstruction technique. The devices employed were Müller ARRR in 24 cases and Burch-Schneider APC in 140. Mean follow-up was 67 months (minimum 12, maximum 123). A total of 4 patients developed deep infection that was treated by resection-arthroplasty. Aseptic loosening of acetabular implant following extensive resorption of bone graft was observed in 5 cases: 3 of the cases underwent acetabular revision. Clinical results were evaluated based on the Harris Hip Score: mean values of 35 and 78 were assessed preoperatively and at follow-up, respectively. X-ray signs of incorporation of bone graft were observed in all cases that progressed successfully.

[Pharmacologic study of the glucocorticoid activity of flunisolide compared with other steroids in the rat]. / Etude pharmacologique de l'activité glucocorticoïde du flunisolide comparativement à d'autres stéroïdes chez le rat.

Flunisolide (FLU), beclomethasone dipropionate (BDP) and its pulmonary metabolites beclomethasone monopropionate (BMP) and beclomethasone (B) were studied in rat for: their relative binding affinity (RBA) for the 5 classes of steroid receptors, their in vitro glucocorticoid activity on rat thymocytes, their in vivo glucocorticoid activity by oral route. These compounds displayed a strong RBA for rat lung, thymus and liver glucocorticoid receptors (FLU > or = BMP > BDP > or = B). They were also shown to have a moderate RBA for both mineralocorticoid and progestin receptors, while being devoid of any binding to androgen and oestrogen receptors. On rat thymocytes FLU exhibited the highest glucocorticoid activity (FLU > B > or = BMP > BDP). In rat oral FLU displayed a strong glucocorticoid activity with a slight first-pass metabolism as opposed to what has been reported in human.

Preoperative autologous blood donation in primary total knee arthroplasty: a single-centre experience on 214 consecutive patients.

BACKGROUND AND OBJECTIVES: Although preoperative autologous blood donation (PABD) is a widespread practice in elective orthopedic surgery, it is controversial whether this procedure avoids allogeneic blood transfusions in patients undergoing total knee arthroplasty (TKA). PATIENTS AND METHODS: We performed a retrospective study on 214 consecutive patients undergoing PABD before elective primary TKA. RESULTS: Thirty-eight patients (17.8%) were transfused with autologous red blood cells (RBC), while four of them (10.5% of those requiring transfusions, 1.9% of all patients) also received allogeneic RBC. The transfused patients were, in most cases, female and had significantly lower basal and preoperative haemoglobin levels. CONCLUSIONS: Based on the results of this study, PABD is not necessary in most patients undergoing TKA, although older female patients with low basal haemoglobin levels could benefit from a predeposit programme and/or erythropoietin support in order to reduce the risk of exposure to allogeneic blood.

RU 41 740 (Biostim) and IL-4, or IL-13, have opposite effects on CD14, CD23, HLA-DR and HLA-DQ on monocytes.

RU 41 740 (Biostim) is a glycoprotein extract obtained from Klebsiella pneumoniae. Its immunostimulating properties on monocytes have been established in vivo and in vitro. To confirm its spectrum of action at molecular level we studied its role on the modulation of four molecules involved in antigen presentation (HLA-DR, HLA-DQ), uptake of endotoxin (CD14) and activation (CD23). These four molecules are known to be modulated by interleukins IL-4 and IL-13. We found that HLA-DR, HLA-DQ, CD14 and CD23 were differentially regulated by biostim and IL-4 or IL-13. Surprisingly, Biostim inhibited the IL-4 or IL-13-induced expression of CD23, HLA-DQ and HLA-DR, while it did not have any action on these molecules by itself. We therefore hypothesize that Biostim, through the action on its receptor, could interact with the IL-4 receptor and IL-13 receptor and/or inhibit the IL-4 and IL-13 receptor transducing signal.

The immunomodulating glycoprotein extract from Klebsiella pneumoniae RU 41740 exerts a suppressive effect on human monocyte death by apoptosis.

Programmed cell death or apoptosis is a physiological cell suicide process that can be suppressed by survival factors. Monocytes undergo rapid apoptosis in culture, unless signalled by cytokines or the bacterial lipopolysaccharide LPS. We have investigated the effect on monocyte apoptosis of the immunostimulating agent RU 41740 (Biostim), a glycoprotein extract from the Klebsiella pneumoniae K2O1 strain that is used for the prevention of recurrent infections. RU 41740, as LPS, strongly enhanced monocyte survival in vitro, an effect related to apoptosis suppression. RU 41740 at concentration ranging from 1 ng/ml to 10 microg/ml prevented apoptosis induced both by survival factor deprival and by gamma-irradiation. Our observation suggests that enhancement of monocyte survival may represent a component of the reported immunostimulating effect of this compound.

RU 41740 (Biostim) stimulates the production of granulocyte macrophage colony-stimulating factor and interleukin-8 by human bronchial epithelial cells in vitro.

1. In this study, we observed the effects of RU 41740 (Biostim) on the production of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-8 (IL-8) in human bronchial epithelial cells in vitro. 2. Cytokine production was assessed by enzyme-linked immunosorbent assay. 3. We report that epithelial cells spontaneously released both cytokines and that RU 41740 induced a significant increase in production of IL-8 and GM-CSF. 4. This is the first observation of a stimulatory effect of an immunostimulating compound used in humans on cytokine production by epithelial cells.

Radial bending breaking resistance derived by densitometric evaluation predicts femoral neck fracture.

Bone mineral density (BMD) measurement by hip dual-energy X-ray absorptiometry (DXA) is considered the best predictor of osteoporotic fracture risk. BMD takes into account only in part the bone cross-sectional area that is an important determinant of both bone compression strength and of bending breaking resistance. From DXA measurements of proximal radius (Osteoplan, NIM, Verona, Italy) we obtained the projected outer diameter (D) and the mean diameter of the medulla (d), by an algorithm based on the assumption of a constant cortical volumetric density of 1050 g/cm3. The algorithm was validated by the good correlation found (r = 0.8) between calculated d and that actually measured by peripheral quantitative tomography (pQCT; XCT 960, Stratec, Unitrem, Italy) at the same radial site. The D and d values were used to calculate a bending breaking resistance index (BBRI) that is a component of the cross-sectional moment of inertia. The BBRI measured in 5460 women aged 35-89 years, was stable up to the age of 65-70 years and rapidly declined thereafter by 0.7% per year. This profile appears to be due to the fact that the increase in medullary area is compensated in terms of mechanical resistance by enlargement of cross-sectional area. In 68 women with either previous femoral neck (n = 41) or pertrochanteric fracture (n = 27) DXA measurements at proximal and ultradistal radius, lumbar spine and femoral neck were obtained together with the evaluation of proximal radius BBRI. The diagnostic accuracy of BBRI was somewhat comparable to that of spine and femoral neck BMD and significantly superior to that of ultradistal and proximal radius BMD, from which it was derived. Despite the obvious limitation of the cross-sectional nature of this study, our results indicate that a simple re-elaboration of the data obtained by peripheral radial densitometry may achieve diagnostic accuracy for hip fracture risk assessment only marginally lower than that of the direct measure of the BMD of the femoral neck. They also give additional support to the view that bone geometry, particularly for compact skeletal segments, is a determinant of its strength at least as important as bone density.

Alteration in the production of free oxygen radicals and proinflammatory cytokines by peritoneal and alveolar macrophages in old mice and immunomodulatory effect of RU 41740 administration. Part I: Effect of short and repetitive noise stress.

The aim of this study was to analyze the effects of stress on natural immunity in old mice, and the potential of an immunomodulating drug to correct stress-induced immune abnormalities. We analyzed both the alveolar (ALM) and peritoneal macrophage (PerM) oxidative responses and cytokine productions of TNF-alpha and IL-1alpha, in old mice after exposure to 3 days of noise stress, with and without treatment with RU 41740, an immunomodulating compound. Production of Free Oxygen Radicals (FOR) by ALM and PerM macrophages was evaluated using a luminol-dependent chemiluminescence method at the basal state and after stimulation. Serum corticosterone was also measured. Three groups of 22-24 month-old C57BL/6 mice were studied. Seven mice were treated with RU 41740 (10 mg kg(-1)) every day for 5 days and then exposed to sound stress (110 dB, 1000 Hz, for 3 nights). Ten mice were treated with saline, then submitted to a sham stress. Eight animals received neither treatment nor stress. There was no difference in corticosterone level between the three groups and between these groups and a control group nonstressed, noncannulated. After stimulation by fMetLeuPhe, production of FOR by ALM and PerM significantly increased after stress and returned to normal values after RU 41740 treatment (p < 0.001). The cytokine levels (TNF-alpha and IL-1alpha) decreased after stress and returned to normal levels after RU 41740 treatment. This study shows that, in aged mice, auditory stress is associated with modifications of macrophage functions which are different, depending on their localization and on the function under study. It confirms the immunomodulatory capacities of RU 41740 that was shown to counteract these effects of stress in elderly animals.